May 2013 e-journal Club
May has been unseasonably cool for Virginia, but at least we escaped any of the spring snowfall that other parts of the country experienced. We had a deluge of rain for the first several days of the traineeship, but the weather cleared up late in the week. This month our trainees hailed from Boston, MA; Braintree, MA; Chapel Hill, NC and Longview, TX. Our journal club article was the long awaited REDOXS study of glutamine and antioxidants in critical illness.
Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013; 368(16):1489-1497.
This was a prospective randomized, double-blind trial of glutamine, antioxidants or the combination of glutamine with antioxidants in mechanically ventilated critically ill patients with two or more organ failures. Study patients received 0.35 g/kg ideal weight of glutamine as intravenous combined with 30 g of glutamine per day given enterally. Antioxidants were provided as 500 μg IV selenium + enteral micronutrients of 300 μg selenium, 20 mg zinc, 10 mg beta carotene, 500 mg vitamin E, and 1500 mg vitamin C. Placebo patients received saline for both enteral and parenteral interventions. The primary outcome of the study was 28-day mortality, and secondary outcomes were ICU length of stay, development of infectious complications, multiple organ dysfunction, duration of mechanical ventilation, length of hospital stay, antibiotic use, and 6 month survival.
Inclusion and Exclusion Criteria were:
Adult patients receiving mechanical ventilation who had two or more organ failures related to their acute illness.
Imminent death or not receiving full aggressive care, absolute contraindication to EN, >24 hours from admit to ICU, severe acquired brain injury (head trauma, SAH, stroke, anoxic brain injury) seizure disorder requiring anticonvulsants, cirrhosis, metastatic cancer or lymphoma with life expectancy < 6 months, uncomplicated elective cardiac surgery, primary admission diagnosis of burns (>30% BSA), weight < 50 kg or > 200 kg, pregnant or lactating with intent to breastfeed, previously in the study or enrolled in another related ICU interventional study.
The investigators screened 5633 patients, of whom 2283 were eligible, 1223 enrolled, with an additional 23 patients enrolled to compensate for those with early death, ICU discharge, or study withdrawal before receiving the supplements. Analysis was completed on 1218 of the 1223 patients that were randomized (per figure 1 of the article).
Overall 28-day mortality was 29.8%. There was a trend toward increased 28-day mortality among patients who received glutamine compared to patients who did not receive glutamine (p=0.05). In-hospital mortality and mortality at 6 months were significantly higher among patients who received glutamine (p= 0.02 both groups). Patients who received glutamine had significantly increased median time to discharge alive from the ICU and median time to discharge alive from the hospital, compared to patients who did not receive glutamine (p=0.03 and 0.04, respectively). Glutamine did not have a significant effect on organ failure outcomes or infections.
There was no significant difference in mortality between patients who received antioxidant supplementation and those who did not. Antioxidant supplementation did not have a significant effect on any secondary outcome compared to no antioxidants. There was no significant interaction identified between glutamine and antioxidants, and there was no significant differences in 28-day mortality in any of the subgroup analyses.
“…this trial showed that the early administration of glutamine in critically ill patients with multi-organ failure was harmful. The observation that the majority of these patients did not have glutamine deficiency early in the course of their critical illness challenges the prevailing concept that glutamine is an essential nutrient that is deficient in critically ill patients and requires immediate supplementation. We also conclude that antioxidant supplementation as provided in this trial conferred no therapeutic benefit.”
This was a very large, multi-center, randomized, double-blind study with analysis of nearly everyone that was randomized. The patients were thought to be the most likely to benefit from the interventions, and there was an enviable compliance with delivery of the study supplements (70.9% of enteral and 89.1% of parenteral prescribed) - especially considering the severity of illness in the population studied. Nonetheless, the results demonstrated that not only was glutamine not helpful, but in the population and doses studied was actively harmful. It would be fair to expect that this study will go down in the annals of nutrition support as an exemplar of why we should not produce, market, or use high-dose nutrients in sick people before we have adequately powered randomized studies.
Our group did discuss several issues that are worth considering when analyzing this study. The first is that the patients in this study received 30 g per day more glutamine than the dose provided in other studies and this is the first study that used both parenteral and enteral glutamine at the same time. The patients in this study were very sick, with many in shock, and glutamine was provided very early in the course of their illness. It will take more large studies to find out if glutamine in lower doses, or to different populations, may be harmful or helpful.
We did note that the investigators choose not to use an isocaloric or isonitrogenous control for the placebo groups. The published protocol for the study noted that there was no evidence, “that a few grams of protein or nitrogen” would impact the survival of critically ill patients. However, the total amount of glutamine was approx. 70 grams (280 kcals)/day – far more than a few grams. The enteral glutamine alone provided an additional 170 calories/day because the enteral dipeptide provided alanine and glycine as well.
The supplemental tables reveal that the actual amount of protein that patients received from enteral and/or parenteral nutrition was very low – only 43 grams/day on average. This suggests that many patients received nearly twice as much glutamine as they did other amino acids. This raises the question if large amounts if glutamine could compete for absorption or utilization with other amino acids; or if preventing muscle breakdown, resulting in less endogenous amino acid delivery to the liver, while providing low amounts of exogenous amino acids might interfere with the formation of acute phase reactants.
The authors point out that that, surprisingly, most of the patients of this study did not have decreased serum glutamine, and that may explain the results. However, this does not automatically mean that glutamine will be beneficial in populations with low serum levels. We know that some serum nutrient levels (such as iron) are decreased as a protective response, and it will take other large randomized studies of different doses and/or routes before we can know if there are populations that may be helped by glutamine.
In terms of the antioxidants, this is another example where the basic science and animal data did not pan out in human studies. Although the doses of some nutrients were not as high as other studies, there remain questions about dose, form of nutrient (alpha-tocopherol vs. gamma-tocopherol and cis/trans B-carotene), appropriate population and timing that will require additional studies.
Our Take Home Message (s)
1. High dose combined enteral-parenteral glutamine appeared detrimental in patients with multi-organ failure, and antioxidants as provided did not appear to have a benefit or harm.
2. Large doses of some seemingly beneficial nutrients can harm some groups of critically ill people, and healthcare professionals entrusted with the care of these sick people should have adequately powered randomized studies before using supplemental nutrients or products with supplemental nutrients.
Other News on the UVAHS GI Nutrition Website: (www.ginutrition.virginia.edu):
Upcoming Webinars 2012/2013:
--June 18: Nutritional Management of Pediatric Food Allergies
--Fall topics to include: Clinical Cases, Nutrition in ALS, and more
Check out What’s New:
Latest Practical Gastroenterology article:
--Newton A, Barnadas G. Understanding Medicare Coverage for Home Enteral Nutrition: A Case-Based Approach. Practical Gastroenterology 2013;XXXVII(5):10.
Joe Krenitsky MS, RD
Carol Rees Parrish MS, RD
PS – Please feel free to forward on to friends and colleagues.